We have developed a chemotherapy regimen (EPOCH) which employs standard drugs for the treatment of recurrent lymphomas but administers the natural products (doxorubicin, vincristine and etoposide) as a 96 hour continuous infusion. The rationale for this approach is based on the in vitro finding that tumor cells exposed to natural products at low doses for prolonged periods are more sensitive then when exposed to high doses for short periods. The trial has two objectives. The first is to assess the efficacy and toxicity of EPOCH in patients with relapsed lymphomas. The results showed EPOCH to be well tolerated with an overall response rate of 80%. The second goal was to assess the therapeutic efficacy of dexverapamil with EPOCH in patients who had progressive or stable disease while receiving EPOCH alone. Dexverapamil was chosen because it is a competitive inhibitor of the mdr- l (p- 170 glycoprotein) drug resistance pump. In the phase I portion of this trial, 65 patients received 130 cycles of dexverapamil/EPOCH chemotherapy, pharmacokinetics and toxicity were determined. Furthermore, the pharmacokinetic interaction of dexverapamil and etoposide and doxorubicin were assessed. In the phase 11 portion of the study, tumors were analyzed for mdr- l expression and the clinical to the addition of dexverapamil to EPOCH was determined. Of 154 patients entered, 64 crossed-over to receive EPOCH/dexverapamil; 54 non-Hodgkin's, and 10 Hodgkin's disease patients. Among non-Hodgkins lymphomas, 7% complete, 5% partial and 12% minor responses with total response rate of 24% was achieved, and among Hodgkin's disease, 20% had partial responses. Of interest was the correlation between mdr- l and response. Of six patients with significantly elevated levels of mdr- l, three responded to dexverapamil, while only l of 8 patients with low mdr- l levels responded. It was also observed that mdr-l expression increased in EPOCH resistant patients. In conclusion, EPOCH was well-tolerated and highly effective in relapsed non-Hodgkin's lymphomas; dexverapamil modestly increased the response rate to EPOCH alone.